Abstract Sjgren's syndrome is a chronic inflammatory autoimmune disease affecting mainly salivary glands and lacrimal glands with an incidence of about 1% in the general population and up to 3% in people above the age of 50, with women accounting for more than 90% of diagnosed cases. Hypofunction of salivary glands or dry mouth is a major symptom of Sjgren's syndrome and severely impairs the quality of life of patients. No effective treatment of Sjgren's syndrome is available now. Mesenchymal stem/stromal cells (MSCs) are conventionally isolated from tissues such as bone marrow, are capable of inhibiting immune responses and inflammation, and have shown therapeutic efficacies in Sjgren's syndrome. However, there are many limitations of using tissue-derived MSCs directly for therapies including their limited expandability, considerable donor variations and variations caused by different expansion methods, and the lack of standard assays for testing therapeutic efficacy of the To overcome these limitations, we have derived MSCs efficiently from human induced pluripotent stem cells (iPSCs) with almost unlimited expandability using a modified protocol that can be easily scaled up to produce very large amounts of standardized MSCs. Our iPSC-derived MSCs showed anti-inflammatory and immunosuppressive effects comparable to tissue-derived MSCs. Nevertheless, there are still many difficulties in clinical application of MSCs such as the need for frozen storage and shipping and to thaw frozen cells, the high cost, and the dynamic changes of live cells. Extracellular vesicles (EVs) are nano- sized particles released from cells spontaneously. EVs carry bioactive molecules similar to their originating cells, and are much safer and more feasible for clinical application compared to their originating cells. MSC EVs showed immunosuppressive activities similar to MSCs in vitro. Our preliminary study indicated that systemically injected iPSC-MSCs or their EVs inhibited the inflammation of salivary gland in a mouse model of Sjgren's syndrome. This proposal aims to determine the potentials and mechanisms of iPSC-MSC EVs in preventing the progression of Sjgren's syndrome using a more faithful mouse model. First, we will determine effects of systemic infusion of iPSC-MSC EVs on preventing progression of Sjgren's syndrome and related changes in immune cells and salivary gland cells. Second, we will determine components of iPSC-MSC EVs essential for preventing progression of Sjgren's syndrome. The success of the proposed research will provide the proof-of-concept for a novel and clinically feasible therapy for Sjgren's syndrome, and will also encourage further research on MSC EVs for improving treatment of a broad range of disorders that have low therapeutic alternatives but share similar inflammatory and/or immune backgrounds including rheumatoid arthritis, inflammatory bowel diseases, graft versus host disease, and rejections of transplants.